| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Herzl Family Practice Centre, ABSTRACT Shrier, Ian, Ari Baratz, and Sheldon Magder. Effects of
adenosine on pressure-flow relationships in an in vitro model of
compartment syndrome. J. Appl.
Physiol. 82(3): 755-759, 1997.
adenosine; vasodilation critical closing pressure; vascular
waterfall; arterial resistance
INTRODUCTION COMPARTMENT SYNDROME is a condition in which an
increase in intramuscular pressure (Pim) compresses blood vessels,
decreases transmural pressure, and limits blood flow (7). In recurrent compartment syndrome (also known as exercise-induced compartment syndrome), Pim increases during exercise. This is believed to cause
ischemic pain that forces the person to stop exercising, and
subsequently Pim slowly returns to normal. Rarely, Pim
continues to increase, and acute compartment syndrome develops (3, 8, 11). This leads to muscle necrosis and permanent disability if not
treated by emergency fasciotomy (3, 8, 11).
We have previously shown that blood flow through the skeletal muscle
circulation is determined by a proximal arterial resistance (Ra) and an
arteriolar vascular waterfall under a variety of conditions (5,
12-14, 16). The term vascular waterfall refers to a back pressure
(Pcrit) at the arteriolar level that dissociates upstream and
downstream flows such that changes in downstream pressure or resistance
have no effect on upstream pressures and there is independent control
of both capillary inflow and outflow.
The waterfall model has important implications regarding the
pathophysiology of recurrent compartment syndrome. We have previously shown that the changes in Pim seen in compartment syndrome can be
modeled by placing the muscle within an airtight box (Pbox) and
changing Pbox. We found that under resting conditions, changes in Pim
decrease flow mostly through changes in Pcrit, with only 15-25%
of the decrease due to changes in Ra (14). However, in recurrent
compartment syndrome, one would expect exercise-induced vasodilation in
the working muscle that could affect the relationship between Pim and
Pcrit. We infused adenosine to mimic exercise-induced vasodilation and
hypothesized that adenosine would affect the slope of the relationship
between Pbox and Pcrit, and between Pbox and Ra, in addition to its
effect on the intercept. In addition, we hypothesized the effect on
Pcrit would be greater than Ra. This is because Pcrit is due to
arteriolar tone, which itself is more tightly coupled to tissue
ischemia than the more proximal vessels responsible for Ra. As flow
decreases with increases in Pim in the absence of adenosine, metabolic
vasodilation should cause the vascular tone to decrease. Therefore,
tone should approach that of adenosine conditions.
METHODS We anesthetized six mongrel dogs weighing 20.1 ± 2.0 kg (mean ± SD) with 30 mg/kg pentobarbital sodium and maintained anesthesia with a
constant infusion of 10-14
mg · kg All animals used in this study were cared for in accordance with the
recommendations of the Canadian Council on Animal Care as interpreted
by the Royal Victoria Hospital Research and Ethics Committee of McGill
University.
Blood flow through
skeletal muscle is best modeled with a vascular waterfall at the
arteriolar level. Under these conditions, flow is determined by the
difference between perfusion pressure (Pper) and the waterfall pressure
(Pcrit), divided by the arterial resistance (Ra). By pump perfusing an
isolated canine gastrocnemius muscle
(n = 6) after it was placed within an
airtight box, with and without adenosine infusion, we observed an
interaction between the pressure surrounding a muscle (as occurs in
compartment syndrome) and baseline vascular tone. We
titrated adenosine concentration to double baseline flow. We measured
Pcrit and Ra at box pressures (Pbox), which resulted in 100 (Pbox = 0),
90, 75, and 50% flow without adenosine; and 200, 180, 150, 100, and
50% flow with adenosine. Without adenosine, each 10% decline in flow
was associated with a 5.7 mmHg increase in Pcrit
(P < 0.01). With adenosine, the same
decrease in flow was associated with a 2.6-mmHg increase in Pcrit
(P < 0.01). Values of Pcrit at 50%
of flow were almost identical. Each 10% decrease in flow was also
associated with 2.2% increase in Ra with or without adenosine
(P < 0.001). Ra decreased with
adenosine infusion (P < 0.05), and
there was no interaction between adenosine and flow (P > 0.9). We conclude that
increases in pressure surrounding a muscle limit flow primarily through
changes in Pcrit with and without adenosine-induced vasodilation. The
interaction between Pbox and adenosine with respect to Pcrit but not Ra
suggests that Pbox affects the tone of the vessels responsible for
Pcrit but not Ra.
1 · h1
pentobarbital sodium (2). The dogs were intubated and
ventilated with oxygen-enriched air by using a Harvard respirator. We
cannulated the left carotid artery to monitor arterial pressure (Pa)
and obtain arterial blood samples. We infused normal saline into the left jugular vein to maintain proper hydration.
PO2, PCO2, and pH were kept in the normal
range with supplemental oxygen, adjustments to the ventilator frequency
and tidal volume, and infusion of sodium bicarbonate as necessary.
Rectal temperature was maintained at 37-39°C with the use of a
heating blanket. A bolus of heparin (10,000 U) was given to prevent
clotting.
Fig. 1.
Schematic diagram of experimental setup. Pper, perfusion pressure;
Pbox, box pressure; Pven, venous pressure. See
METHODS for details.
[View Larger Version of this Image (24K GIF file)]
Pcrit)/flow.
Statistics.
Multiple-regression analysis was used to determine the relationship
between the independent variables, Pbox, animal, and adenosine, and the
dependent variables, flow, Pcrit, and Ra.
RESULTS
The PCO2 was 36.2 ± 3.3 (SD)
Torr, and PO2 was 168 ± 32 Torr.
Rectal temperature was 37.4 ± 1.1°C, and hemoglobin was 12.9 ± 2.0 g/dl. The hydrogen concentration was 4.16 ± 0.51 × 108 M, pH 7.38.
Baseline flow was 7.6 ± 0.7 ml · min1 · 100 g1 (mean ± SE, Pper = 114 ± 8 mmHg, Pbox = 0 mmHg) without adenosine, and 14.7 ± 1.5 ml · min1 · 100 g1 with adenosine (Pper = 112 ± 9 mmHg, Pbox = 0 mmHg). Flow decreased as Pbox increased, and
the rate of decrease was greater with adenosine (Fig.
2). The overall equation for the
relationship is
|
) and with
adenosine-induced vasodilation (
; n = 6). Flow decreased with increases in Pbox, and the decrease was
greater during adenosine conditions.
To show the importance of the waterfall model, we have first shown the
relationship between total resistance (Rtot) across the muscles'
vascular bed [calculated according to the nonwaterfall-model equation
Rtot = (Pper Pv/flow] and %flow (Fig.
3). The relationship is curvilinear, and
because Pper, Pv, and flow are the same at each %flow with and without
adenosine, the data points for the two conditions superimpose.
) and with
adenosine-induced vasodilation (; n = 6).
Figure 4 shows the relationship between
%flow and Ra, and Fig. 5 shows the
relationship between %flow and Pcrit. Both dependent variables are
calculated according to the waterfall model equations. These graphs
illustrate that the curvilinear relationship of
RT vs. %flow can be broken down
into two linear components.
) and with adenosine-induced vasodilation (;
n = 6). Adenosine decreased Ra at each
%flow, despite much higher Pbox under adenosine conditions. Slopes of
relationships were similar (P > 0.9).
) and with adenosine-induced vasodilation (;
n = 6). Pcrit decreased with
adenosine-induced vasodilation at the same Pbox (Pbox = 0, 100% flow
without adenosine, and 200% flow with adenosine). However, Pcrit is
higher at same %flow because of much higher Pbox under adenosine
conditions. Rate of increase of Pcrit with decreases in flow was
greater under control conditions (P < 0.001).
Ra without adenosine at Pbox = 0 and Pper = 113 mmHg was 7.3 ± 1.1 mmHg · min · 100 g · ml1
(flow = 100%), and with adenosine it decreased to 4.7 ± 0.6 mmHg · min · 100 g · ml1
(flow = 200%). Figure 4 shows that Ra increased slightly as flow decreased secondary to the increase in Pbox. The overall equation is
|
Pcrit without adenosine at Pbox = 0 and Pper = 113 mmHg was 61.7 ± 6.4 mmHg, and with adenosine it decreased to 47.6 ± 8.8 mmHg. Figure 5 shows that Pcrit increased substantially as flow decreased secondary to the increase in Pbox. The overall equation is
|
DISCUSSION
Our results suggest that low doses of adenosine increase flow mainly through a decrease in Ra, with a smaller effect on the vascular waterfall itself (Pcrit). In addition, there is an interaction between Pbox and adenosine with respect to Pcrit but not with respect to Ra. Note that the effects of adenosine on different parts of the vasculature according to the waterfall model are not evident in the classical curvilinear relationship of Rtot vs. %flow.
We have previously discussed the limitations of our technique (12, 14) and will briefly summarize the principles below. Pcrit observed in these experiments occurred in isolated muscle and therefore cannot be due to collateral circulation (9, 10). The effects of compliance on the measurement of Pzf are minimized with our ramp technique, and under these conditions, Pzf is a good estimate of Pcrit (1, 4, 5, 12, 14). Although the muscle was perfused with blood from animals with constant rectal temperature, the fact that the box was room temperature might have affected the quantitative changes observed. However, it is unlikely that it affected the qualitative changes. Because all neural connections had to be severed, changes in the pressure surrounding the muscle could not have induced changes in vasomotor tone through any systemic neural or hormonal reflexes. Finally, our Pper measurement was really a side pressure that is lower than end pressure at higher flows due to the Bernouille effect. This means that the increased flow with adenosine at the same Pper was partly due to an increase in end-pressure Pper and not only due to adenosine-induced vasodilation. Because an increase in Pper is associated with an increase in Pcrit (15), and we observed a decrease in Pcrit with adenosine in the present study, using end pressure would only have increased the quantitative results we obtained.
Interaction between adenosine and Ra. At Pbox = 0, adenosine increased flow through a 36% decrease in Ra and a 23% increase in driving pressure due to a decrease in Pcrit. The small increase in Ra with decreases in flow (secondary to vessel compression from the decrease in transmural pressure caused by the increase in Pbox) supports our previous findings (14) and those of Meininger et al. (6) who found very little change in large vessel diameter in vivo over a wide range of transmural pressures. When Pbox was increased to decrease flow, Ra increased at the same rate with or without adenosine. This suggests that decreases in transmural pressure caused by increases in Pbox have very little effect on the "tone" of the vessels responsible for Ra. For instance, if increases in Pbox caused a decrease in vasomotor tone of the vessels responsible for Ra, then vasomotor tone without adenosine should approach that with adenosine. This would be reflected by a difference in slopes in Fig. 4. The finding of parallel relationships under the two conditions suggests that proximal arterial tone is unaffected by vessel compression for the range of %flow studied. It is possible that the relationship would have proved curvilinear at lower flows. Interaction between adenosine and Pcrit. At the same percent flow, Pcrit was greater with adenosine compared with control conditions. This occurred because the small decrease in Pcrit with adenosine-induced vasodilation was more than offset by the increase in Pcrit that occurred when Pbox was increased to return flow to control values. Therefore, Pcrit was greater at the same flow with adenosine. Figure 5 shows that there was a steeper rise in the Pcrit vs. %flow relationship without adenosine. This may seem counterintuitive, as vessels with more tone should theoretically be less easily compressed. However, it occurs because Pcrit is due to the combination of changes in transmural pressure and vascular tone. As Pbox is increased to cause a decrease in flow, vessels become compressed secondary to the decrease in transmural pressure, Pcrit increases, and ischemia causes vascular tone to decrease secondary to autoregulation. However, autoregulation has less effect if adenosine has already dilated the vessels. Therefore, Pcrit under the two conditions should approach each other, and at 50% of baseline flow, Pcrit was equal under both conditions. This does not mean that vessel tone is identical under the two conditions. In Fig. 2, Pbox at 50% flow with adenosine is 38.3 ± 5.1 compared with 28.8 ± 2.4 mmHg without adenosine. If Pcrit is due to a combination of mechanical compression (i.e., Pbox) and arteriolar tone, and Pbox was greater with adenosine at the same Pcrit (i.e., 50% flow), then tone must have been less. This effect may have been abolished at lower flows and more severe ischemia, but the technical limits of our pump-perfusion system did not allow us to measure Pcrit at lower flows. Our hypothesis that the rate of rise of Pcrit is decreased when the tone of the vessels is decreased is supported by our previous work (14). For instance, if one compares the tone of the vessels with and without adenosine in the present experiment, with the tone of the vessels in our previous experiment (14), one finds that the tone was highest in the present experiments without adenosine (flow = 7.6 ± 0.7 ml · min1 · 100 g1, Pper = 114 mmHg), next
highest in control experiments in our previous study (flow = 11.6 ± 1.3 ml · min1 · 100 g1, Pper = 97 mmHg), and
lowest with adenosine in the present experiment (flow = 14.7 ± 1.5 ml · min1 · 100 g1, Pper = 112 mmHg). The
slope of the Pcrit vs. %flow relationship followed a similar pattern
(5.7 vs. 3.8 vs. 2.6 mmHg per 10% decrease in flow).
Clinical relevance.
Although Pcrit and Ra are affected equally by sympathetic stimulation
(12), the present results support our previous findings (12, 14, 15)
that Ra and Pcrit can also be affected independently of each other. For
instance, changes in transmural pressure affect mostly Pcrit, whether
they occur by changes in intravascular (14) or extravascular pressure
(16). On the other hand, adenosine caused a larger fall in Ra compared
with the effects on Pcrit. A similar result was obtained with
nifedipine in a previous study (16). Because both of these
pharmacological interventions have a relatively greater effect on Ra,
they do not diminish the beneficial aspects of the vascular waterfall
phenomenon (5). These include the absence of variations in flow with
changes in venous pressure or venous resistance, and a smaller fall in
Pa with sudden decreases in cardiac output.
In compartment syndrome, the pressure surrounding a muscle is
increased. This increase in pressure will cause compression of the
vessels and decrease flow, and finally autoregulation will cause a
decrease in vascular tone. As occurs in the intact human subject, the
perfusion pressure was kept at the normal level in our ex- periments.
The present results suggest that infusion of adenosine should increase
flow for any given Pim (Fig. 2). However, the effect of adenosine
becomes much less important at very low flows. The methods of our study
limited us to studying decreases in flow to 50% of baseline flow,
which corresponded to a Pbox of <40 mmHg. In recurrent
compartment syndrome, the mean relaxation pressure (in between
contractions) is also ~40 mmHg (17), but the muscle is metabolically
active, and therefore the tone of the vasculature is probably much less
than the tone during the small amount of vasodilation in the present
experiment. Because our study results suggest that the effect of
vasodilators is minimal at high Pbox, it is unlikely that vasodilators
would be useful in prevention of symptoms in these patients.
In conclusion, adenosine-induced vasodilation increases flow mainly
through a decrease in Ra, with smaller changes in Pcrit. An increase in
the pressure surrounding the muscle causes a decrease in flow mainly
through an increase in Pcrit, with smaller changes in Ra. The results
also suggest that for the range studied, increases in the pressure
surrounding a muscle cause a local decrease in vasomotor tone of the
small vessels responsible for Pcrit but no change in vasomotor tone for
the more proximal vessels responsible for Ra.
ACKNOWLEDGEMENTS
The authors thank Stephen Nuara for technical assistance.
FOOTNOTES
Address for reprint requests: I. Shrier, Herzl Family Practice Centre, Rm. E-0010, Sir Mortimer B. Davis Jewish General Hospital, 5757 Legare, Montreal, Quebec, Canada H3T 1Z6.
Received 16 January 1996; accepted in final form 2 October 1996.
REFERENCES
| 1. | Aversano, T., F. J. Klocke, R. E. Mates, and J. M. Canty, Jr. Preload-induced alterations in capacitance-free diastolic pressure-flow relationships. Am. J. Physiol. 246 (Heart Circ. Physiol. 15): H410-H417, 1984. |
| 2. |
Baum, D.,
J. B. Halter,
G. J. Taborsky, Jr.,
and
D. Porte, Jr.
Pentobarbital effects on plasma catecholamines: temperature, heart rate, and blood pressure.
Am. J. Physiol.
248 (Endocrinol. Metab. 11):
E95-E100,
1985.
|
| 3. | Blandy, J. P., and R. Fuller. March gangrene. J. Bone Jt. Surg. Br. Vol. 39-B: 679-693, 1957. |
| 4. |
Eng, C.,
J. H. Jentzer,
and
E. S. Kirk.
The effects of the coronary capacitance on the interpretation of diastolic pressure-flow relationships.
Circ. Res.
50:
334-341,
1982.
|
| 5. |
Magder, S.
Starling resistor versus compliance. Which explains the zero-flow pressure of a dynamic arterial pressure-flow relation?
Circ. Res.
67:
209-220,
1990.
|
| 6. |
Meininger, G. A.,
C. A. Mack,
K. L. Fehr,
and
H. G. Bohlen.
Myogenic vasoregulation overrides local metabolic control in resting rat skeletal muscle.
Circ. Res.
60:
861-870,
1987.
|
| 7. | Mubarak, S. J. A practical approach to compartmental syndromes: Part II. Diagnosis. Instr. Course Lect. 32: 92-102, 1983. [Medline] |
| 8. | Pearson, C., R. D. Adams, and D. Denny-Brown. Traumatic necrosis of pretibial muscles. N. Engl. J. Med. 239: 213-217, 1948. [Medline] |
| 9. |
Scheel, K. W.,
H. Mass,
and
S. E. Williams.
Collateral influence on pressure-flow characteristics of coronary circulation.
Am. J. Physiol.
257 (Heart Circ. Physiol. 26):
H717-H725,
1989.
|
| 10. |
Scheel, K. W.,
H. Mass,
and
S. E. Williams.
Pressure-flow characteristics of intramural and total coronary collateral networks.
Am. J. Physiol.
264 (Heart Circ. Physiol. 33):
H408-H412,
1993.
|
| 11. | Shrier, I. Exercise-induced acute compartment syndrome: a case report. Clin. J. Sport Med. 1: 202-204, 1991. |
| 12. |
Shrier, I.,
S. N. A. Hussain,
and
S. Magder.
Effect of carotid sinus stimulation on resistance and critical closing pressure of the canine hindlimb.
Am. J. Physiol.
264 (Heart Circ. Physiol. 33):
H1560-H1566,
1993.
|
| 13. |
Shrier, I.,
and
S. Magder.
NG-nitro-L-arginine and phenylephrine have similar effects on the vascular waterfall in the canine hindlimb.
J. Appl. Physiol.
78:
478-482,
1995.
|
| 14. |
Shrier, I.,
and
S. Magder.
Pressure-flow relationships in an in vitro model of compartment syndrome.
J. Appl. Physiol.
79:
214-221,
1995.
|
| 15. |
Shrier, I.,
and
S. Magder.
Response of arterial resistance and critical pressure to changes in perfusion pressure in the canine hindlimb.
Am. J. Physiol.
265 (Heart Circ. Physiol. 34):
H1939-H1945,
1993.
|
| 16. |
Shrier, I.,
and
S. Magder.
The effects of nifedipine on the vascular waterfall and arterial resistance in the canine hindlimb.
Am. J. Physiol.
268 (Heart Circ. Physiol. 37):
H371-H376,
1995.
|
| 17. | Styf, J., L. Kürner, and M. Suurjula. Intramuscular pressure and muscle blood flow during exercise in chronic compartment syndrome. J. Bone Jt. Surg. Br. Vol. 69-B: 301-305, 1987. |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
ABSTRACT